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Platelet rich clots are resistant to lysis by thrombolytic therapy in a rat model of embolic stroke.

Tomkins AJ, Schleicher N, Murtha L, Kaps M, Levi CR, Nedelmann M, Spratt NJ - Exp Transl Stroke Med (2015)

Bottom Line: Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7).Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction.These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.

ABSTRACT

Background: Early recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. Microbubble-enhanced sonothrombolysis is a promising therapy to improve recanalization rates and reduce the time to recanalization. Testing any thrombolytic therapy requires a model of thromboembolic stroke, but to date these models have been highly variable with regards to clot stability. Here, we developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA). This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis.

Methods: In Study 1 we investigated spontaneous recanalization rates of PRC in vivo over 4 hours and measured infarct volumes at 24 hours. In Study 2 we investigated tPA-mediated thrombolysis and microbubble-enhanced sonothrombolysis in this model.

Results: Study 1 demonstrated stable occlusion out to 4 hours in 5 of 7 rats. Two rats spontaneously recanalized at 40 and 70 minutes post-embolism. Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7). In Study 2, recanalization was not observed in any of the groups post-treatment.

Conclusions: Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction. These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis. This resistance of platelet rich clots to enhanced thrombolysis may explain recanalization failures clinically and should be an impetus to better clot-type identification and alternative recanalization methods.

No MeSH data available.


Related in: MedlinePlus

Laser Doppler flowmetry (LDF) of regional cerebral blood flow in treatment groups (Study 2). Animals underwent embolization of the middle cerebral artery (MCA) with platelet rich clot. LDF confirmed occlusion in all animals and indicated no recanalization post-treatment. Data represents the mean of n = 10 per group. There were no significant differences between groups. (U/S = ultrasound; BR38 = microbubbles).
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Fig3: Laser Doppler flowmetry (LDF) of regional cerebral blood flow in treatment groups (Study 2). Animals underwent embolization of the middle cerebral artery (MCA) with platelet rich clot. LDF confirmed occlusion in all animals and indicated no recanalization post-treatment. Data represents the mean of n = 10 per group. There were no significant differences between groups. (U/S = ultrasound; BR38 = microbubbles).

Mentions: A total of 4 animals were excluded due to SAH (n = 2, determined post-mortem), excessive bleeding pre-embolism (n = 1), and catheter dislodgement during treatment (n = 1). These animals were replaced so that all groups consisted of 10 animals. No animals recanalized in any treatment group in Study 2 (Figure 3 and see Additional file 1). Clot was visible within the Circle of Willis of all animals except one in the ultrasound group, however clot was observed in the distal MCA of this animal (Figure 1 and see Additional file 1).Figure 3


Platelet rich clots are resistant to lysis by thrombolytic therapy in a rat model of embolic stroke.

Tomkins AJ, Schleicher N, Murtha L, Kaps M, Levi CR, Nedelmann M, Spratt NJ - Exp Transl Stroke Med (2015)

Laser Doppler flowmetry (LDF) of regional cerebral blood flow in treatment groups (Study 2). Animals underwent embolization of the middle cerebral artery (MCA) with platelet rich clot. LDF confirmed occlusion in all animals and indicated no recanalization post-treatment. Data represents the mean of n = 10 per group. There were no significant differences between groups. (U/S = ultrasound; BR38 = microbubbles).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318170&req=5

Fig3: Laser Doppler flowmetry (LDF) of regional cerebral blood flow in treatment groups (Study 2). Animals underwent embolization of the middle cerebral artery (MCA) with platelet rich clot. LDF confirmed occlusion in all animals and indicated no recanalization post-treatment. Data represents the mean of n = 10 per group. There were no significant differences between groups. (U/S = ultrasound; BR38 = microbubbles).
Mentions: A total of 4 animals were excluded due to SAH (n = 2, determined post-mortem), excessive bleeding pre-embolism (n = 1), and catheter dislodgement during treatment (n = 1). These animals were replaced so that all groups consisted of 10 animals. No animals recanalized in any treatment group in Study 2 (Figure 3 and see Additional file 1). Clot was visible within the Circle of Willis of all animals except one in the ultrasound group, however clot was observed in the distal MCA of this animal (Figure 1 and see Additional file 1).Figure 3

Bottom Line: Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7).Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction.These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.

ABSTRACT

Background: Early recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. Microbubble-enhanced sonothrombolysis is a promising therapy to improve recanalization rates and reduce the time to recanalization. Testing any thrombolytic therapy requires a model of thromboembolic stroke, but to date these models have been highly variable with regards to clot stability. Here, we developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA). This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis.

Methods: In Study 1 we investigated spontaneous recanalization rates of PRC in vivo over 4 hours and measured infarct volumes at 24 hours. In Study 2 we investigated tPA-mediated thrombolysis and microbubble-enhanced sonothrombolysis in this model.

Results: Study 1 demonstrated stable occlusion out to 4 hours in 5 of 7 rats. Two rats spontaneously recanalized at 40 and 70 minutes post-embolism. Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7). In Study 2, recanalization was not observed in any of the groups post-treatment.

Conclusions: Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction. These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis. This resistance of platelet rich clots to enhanced thrombolysis may explain recanalization failures clinically and should be an impetus to better clot-type identification and alternative recanalization methods.

No MeSH data available.


Related in: MedlinePlus